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Airway epithelial cells harbor the capacity of active Cl−transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl−accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl−concentration ([Cl−]i) was increased after Pseudomonas aeruginosalipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)–phosphodiesterase 4D (PDE4D)–cAMP signaling pathways. Clamping [Cl−]iat high levels or prolonged treatment with LPS augmented serum- and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-κB activation in airway epithelial cells, whereas inhibition of SGK1 abrogated airway inflammation in vitro and in vivo. Furthermore, Cl−–SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H2S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl−]ivia activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl−is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl−may offer novel targets for the management of airway inflammatory diseases.